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Research News

Amjad Javed and Haiyan Chen examine the effect of a runx2 deletion on bone mineralization.

Amjad Javed, Ph.D., of the University of Alabama at Birmingham, has taken a major step forward in understanding the bone development function of a gene called runx2, which could lead to future ways to speed bone healing, aid bone bioengineering, stem osteoporosis and reduce arthritis.

Javed, a professor in the UAB School of Dentistry’s Department of Oral and Maxillofacial Surgery, says the results will contribute to future personalized medicine. This month, Javed presented this work to a standing-room-only audience at the International Association for Dental Research Annual Meeting in Boston. The work was published recently in two articles in the Journal of Bone and Mineral Research.

It was well-known that the deletion of both copies of the runx2 gene is lethal and the organism cannot form bone, teeth or cartilage.

To learn about the function of runx2 in specific cells types, Javed and his colleagues developed mice in which both copies of the runx2 gene were removed in only one of two key cells for bone tissue — either chondrocytes or osteoblasts.

“Our objective was to dissect and tease out which cell is really contributing what in bone development,” Javed said. “Runx2 is vital. But when we talk up personalized medicine, we need to identify which specialized cells to target within bone tissue.”

Study of these mice (technically known as the next-generation conditional knockout runx2 model) shows that chondrocytes and osteoblasts have surprisingly different functions in bone formation during gestation or after birth:

Chondrocytes are involved in bone mineralization during embryonic development.

Osteoblasts are involved in bone growth during postnatal developmentThis is a major step forward in understanding the biology of bones — the dynamic, complex organs that are actively remodeled throughout life. Bones have cartilage-producing cells (chondrocytes), bone-creating cells (osteoblasts), bone-eating cells (osteoclasts), neuronal cells and blood-forming (hematopoietic) cells. Connective tissue and muscle surround the bones.

A chondrocyte specific runx2 homozygous mouse at embryogenesis period E18 (right) has cartilage tissue (stained light blue) but a nearly complete lack of endochondral ossification (the purple stain seen in the control mouse, left). This lack of bone mineralization is especially noticeable in the spinal column, ribs and legs that are initially generated by chondrocytes.

Chondrocytes

Javed’s model began with the cartilage-producing cells. “We first removed the runx2 gene in chondrocytes, cells that are fundamental for every cartilage tissue in the body,” Javed said. “Our first surprise was lethality at birth.”

The skull of the mouse neonates was normal (skull bones are formed through a different bone-creation process); but the cartilage of all the other bones in the body failed to mature and get replaced by mineralized bone, a process known as endochondral ossification. So runx2, which had previously been thought to function only in the developing terminally mature chondrocyte, now appears to act earlier.

Without the runx2 gene, chondrocytes are unable to proliferate and differentiate into the column of cells needed for bone formation and lengthening. The deletion mutant showed that runx2 directly regulates a unique set of four cell-cycle genes to control the proliferative capacity of chondrocytes. The runx2 mutant mice also suffered dwarfism due to a near absence of a proliferative zone in the growth plates of bones.

Osteoblasts

When Javed’s group removed runx2 in osteoblast cells, the results were again surprising. “Here we expected lethality,” Javed said. “To our surprise, they were born alive. When we saw that, we thought it was a mistake. We started questioning, ‘What happened?’”

It had been thought that the runx2 mutation would prevent the osteoblasts from differentiating into their final developmental stage of mature osteoblasts, and thus leave the mice boneless. But the results showed that the runx2 gene is not essential after the cells have already committed to becoming mature osteoblasts. Thus, most of the bones of the mice developed normally, though they had poor calcification.

The exception was the skull, which is formed through a different bone-creation process (intramembranous ossification). The skulls of the runx2 mutant mice had open fontanelles and sutures — the soft spots of the head between the six plates of the skull, spots that are supposed to fuse into bone after birth. Open fontanelles are one of the hallmarks seen in the human hereditary congenital disorder cleidocranial dysplasia (CCD), caused by a heterozygous runx2 mutation; but the mice did not show the other hallmark of human CCD, a missing collarbone. Lacking a collarbone, CCD patients are able to touch their shoulders together in front of their chest.

“Then, we had an additional surprise,” Javed said of the mice with runx2 deletion in osteoblasts. “It is the postnatal skeletal growth that is affected. The mouse starts normally, but by three months of age — which is equivalent to 18-21 years in humans — the mice had 30 percent less weight than wild-type mice.”

The runx2 mutation in osteoblasts caused poor alignment of the collagen scaffold that provides structural strength to mineralized bone. This left the bones brittle, less stiff and prone to fractures. As an additional surprise, the runx2 mutation in osteoblasts caused a significant reduction in osteoclasts (the bone-eating cells that work together with osteoblasts in bone remodeling).

The runx family

Runx2 — as well as two related genes called runx1 and runx3 — is a master transcription factor that controls at least a thousand other genes. The developmental impact of these runx genes (pronounced either “runks” or “run-ex”) has long been known by making deletion mutants of each gene. These deletion-mutants are lethal during gestational development, but each master transcription factor controls a very different tissue.

While runx2 controls bone, teeth and cartilage, organisms with loss of the runx1 gene suffer problems in hematopoiesis. A deletion of runx3 gene leads to hyperplasia of the gastrointestinal tract.

Javed’s colleagues in the runx2 work, which took three years to fully develop and test, are Haiyan Chen, M.D., Ph.D., Farah Ghori-Javed, M.D., Harunur Rashid, Ph.D., Mitra Adhami Ph.D., and John Clarke, all of the Department of Oral and Maxillofacial Surgery, Institute of Oral Health Research in the UAB School of Dentistry; Rosa Serra, Ph.D., of the UAB Department of Cell, Developmental and Integrative Biology, UAB School of Medicine; Yang Yang, M.D., Ph.D., of the UAB Division of Molecular and Cellular Pathology, UAB Department of Pathology in the UAB School of Medicine; and Soraya Gutierrez, Ph.D., of the Universidad de Concepción, Chile, Departamento do Bioquímica y Biología Molecular.

“Palliative care is about providing an extra layer of support so that patients can live well and families can be supported,” said principal investigator Marie Bakitas, D.N.Sc., professor and Marie L. O’Koren Endowed Chair in the School of Nursing. “These data support the importance of providing this care at the same time as medical treatments aimed at fully curing disease. Too often, that is not the case.”

“If patients and clinicians wait to introduce palliative care when a person is actively dying, it limits the full range of services that patients and their families can receive,” said Nick Dionne-Odom, Ph.D., postdoctoral fellow in the School of Nursing and lead author of the family caregiver ENABLE Trial outcomes. “This means palliative care is mistakenly associated solely with end-of-life care. This is unfortunate. Our research shows that integration of palliative care earlier in the cancer trajectory benefits both patients and their family caregivers.”

“These data support the importance of providing this care at the same time as medical treatments aimed at fully curing disease. Too often, that is not the case.”

The investigators say that family caregivers who receive this support and education have greater capacity and skills to deliver high-quality support to patients. Likewise, providing patients with palliative care early eases the burden on families, who deliver the majority of care and psychosocial support in the home.

“Anyone who has been through cancer with a family member can attest to the physical, psychological and existential burden it places on both parties,” Dionne-Odom said. “Receiving this extra layer of support early and at the same time as curative medical treatments is vital for helping patients and their family caregivers develop the coping and other skills needed for the ups and downs of their journey.”

Bakitas says two other shifts in the view of palliative care also are needed.

“Reimbursement mechanisms need to incentivize this care to be offered regardless of six-month prognosis, which is the current hospice-benefit requirement,” Bakitas said. “Also, increased clinician education is needed to train both specialists and general practitioners in palliative care.”

Both researchers say mechanisms still need to be identified that explain the effects of early palliative care, and they are looking at the impact of depression and biological mechanisms that might contribute to this explanation.

Bakitas recently was awarded a five-year, $3.5 million National Institute of Nursing Research R01 grant to study whether palliative care provided to advanced heart-failure patients while they are well results in a better quality of life, improved mood, and less symptom distress/burden for patients and/or caregivers when compared to usual heart-failure care. It will test this similar intervention using materials and an approach adapted from the ENABLE cancer intervention.

This syndrome — acquired thrombotic thrombocytopenic purpura, or TTP — produces blood clots in small arterioles throughout the body, particularly in the brain, heart, pancreas and kidneys. The most effective treatment thus far is daily plasma exchange, with replacement of all or one and a half times the body’s entire blood volume. Such treatment costs nearly $10,000 a day and may need to be continued for weeks or, in some patients, months.

Zheng and colleagues have now developed a potential novel way to treat acquired TTP. Their approach not only could slash the amount of plasma transfusion needed for TTP patients, but also could become a new emergency therapy for strokes, heart attacks, malignant malaria and pre-eclampsia. All are associated with relative deficiency of plasma ADAMTS13 activity. The work, now a proof-of-concept in a mouse TTP model, has been published online this week in the journal Blood.

TTP is an autoimmune disorder — people produce an autoantibody that inactivates an enzyme called ADAMTS13. Of note, Zheng was the first scientist to clone ADAMTS13. That enzyme normally acts to cleave von Willebrand factor, a large protein involved in blood clotting. The loss of ADAMTS13 activity due to autoantibody in TTP patients allows formation of the destructive microvascular clots in many important organ tissues.

Zheng had an idea of how treat TTP: “Hide the enzyme inside cells where the antibody can’t see it.”

His cells of choice were platelets, tiny blood cells a fifth the diameter of a red blood cell.

The normal function of a platelet is to stop bleeding from blood vessels. “When the platelet sticks to the injured site, it gets activated, changes its shape and releases its contents,” said Zheng. “It’s like a mini-bomb.”

Zheng reasoned that, if he could fill the platelets with ADAMTS13, the platelets would then carry the enzyme right to the place it was most needed to dissolve the TTP clots.

For the proof-of-concept, his research group developed transgenic mice that expressed functional recombinant human ADAMTS13 (rADAMTS13) in mouse platelets.

The group then showed that:

The platelets with the human rADAMTS13 had normal agglutination and aggregation.

The platelets released rADAMTS13 upon stimulation with clot inducers.

The mice with rADAMTS13 inside platelets were significantly protected in a vascular injury model of thrombus formation.

The same mice were protected against bacterial toxin or recombinant von Willebrand factor-induced TTP due to hereditary deficiency of ADAMTS13, a genetic disease where an offspring makes little or no ADAMTS13 (although hereditary TTP is much rarer than acquired TTP).

These mice were also protected against antibody-mediated TTP after being challenged by recombinant von Willebrand factor.

All of these findings of the study, they conclude, “suggest that platelets may be ideal carriers for antithrombic ADAMTS13, allowing its release at high concentrations at the site of thrombus formation without being inactivated by the potential circulating anti-ADAMTS13 inhibitors.”

Of course, genetic engineering or biochemical approaches would not be used to apply this proof-of-concept to human TTP patients. Zheng says one approach will be to learn how to pack ADAMTS13 inside the human platelets during the time that bags of donated blood sit at room temperature for three days as they are tested for multiple infectious disease markers. These packed platelets would then be tested to learn how many ADAMTS13-loaded platelets need to be transfused to get anti-blood clot and anti-TTP effects in patients with acquired TTP. Platelets do not have nuclei, and they lack the blood type ABO antigen markers found on red blood cells.

Curtis A. Carver Jr., Ph.D., comes to UAB from the Board of Regents of the University System of Georgia, where he served as vice chancellor and chief information officer.

Curtis A. Carver Jr., Ph.D., has been named the next vice president of Information Technology/chief information officer of the University of Alabama at Birmingham. Carver comes to UAB from the Board of Regents of the University System of Georgia, where he served as vice chancellor and chief information officer.

In his new role, Carver will serve as the senior IT leader at UAB, provide the strategic management and vision to guide the future direction of IT in support of the administrative, academic and research missions of UAB, and oversee the central IT organization in collaboration with the Health System Information Systems unit.

The VP IT/CIO reports directly to UAB President Ray L. Watts.

“Dr. Carver has a terrific background and reputation, and we are thrilled that he will be joining UAB,” Watts said. “This position is vitally important because IT touches all areas of the institution, and I want to thank the search committee that worked diligently to lead a national search and identify fantastic candidates. Dr. Carver is a great fit for UAB.”

Carver, who will lead development of a transparent, high-performing central IT organization with a culture of providing first-rate customer service and implementing reliable, state-of-the art technologies, is looking forward to moving to his transition.

“I am honored and excited to join the UAB team as it seeks to simply change the world,” Carver said. “Information technology can enable and empower that change by facilitating the work of others and creating business value. I look forward to moving to Birmingham, listening intently and setting about the work worth doing of enhancing the experiences of all members of the UAB family.”

With the proliferation of big data computing in research, UAB IT will play a critical role in expanding UAB’s research capabilities across campus.

“I am excited Dr. Carver has accepted the VP IT/CIO position at UAB,” said Hemant Tiwari, Ph.D., head of the Section on Statistical Genetics in the School of Public Health and faculty representative on the search committee. “I am looking forward to working with him in strengthening Research IT to meet the demands of current and future needs of research scientists at UAB. I have full confidence in Dr. Carver to find the optimal solution to meet the needs of big data research at UAB.”

Carver, who will lead development of a transparent, high-performing central IT organization with a culture of providing first-rate customer service and implementing reliable, state-of-the art technologies, is looking forward to moving to his transition.

In addition to his role in IT, Carver’s extensive experience will benefit UAB students in the classroom. He has a passion for teaching and will hold an academic appointment in Computer Sciences.

Prior to joining the University System of Georgia, Carver served at the U.S. Military Academy – West Point in a number of positions, including interim vice dean of Education, vice dean for Resources, associate dean for Academic Computing and IT program director.

Carver’s 27-year military career includes appointments as platoon leader, senior signal officer, company commander, battalion operations officer, division deputy G6 and military mentor. He has lived in Korea and Italy and was deployed to Afghanistan and Iraq, where he served as a strategic mentor to build their respective national military academies.

Throughout his career, Carver has been engaged in the active leadership of military, academic, research and service organizations. He has served as a member of a number of governing bodies or executive boards, including the Computer Science Accreditation Board, Computer Accreditation Commission, multiple CIO Executive Summits and the Federal Information Assurance Conference. He is a senior-level member in the Association for Computing Machinery and the Institute of Electrical and Electronics Engineers professional societies and continues to play an active role in shaping the national agenda in technology, education and the interaction between the two. In 2012, Carver received the Global CIO Break Away Leader Award.

Carver has written many journal articles and conference papers, as well as hundreds of plenary presentations, and is a frequent keynote presenter. He has received numerous national and international honors and awards for military, teaching and research excellence throughout his career.

Carver’s first day at UAB will be June 1. The VP IT/CIO role was vacated in 2014 and has been filled on an interim basis by Jeff Neyland.

“We are very grateful to Jeff for his leadership, vision and dedicated service in leading IT,” Watts said. “He was instrumental in helping us assess our needs for the department and its next leader. We are confident we have identified a great fit for UAB IT.”

Women’s Choice Award is a consumer advocacy group that helps women make smart health care decisions by identifying where they can get the very best care. It is the only program that identifies the nation’s best in health care based on patient satisfaction, clinical excellence, and what women really want when it comes to treatment and a high-quality medical experience.

“It is an honor to have this distinction bestowed on us, as it comes from the voice of women,” said Helen Krontiras, M.D., surgical oncologist and co-director of the UAB Breast Health Center. “When women choose to come to UAB, they can be assured that we have met the highest standards in caring for the needs of our female patients.”

UAB was selected because it met the rigorous standards and measures of excellence from the National Accreditation Program for Breast Centers from the American College of Surgeons, carries the Seal of the American College of Radiologists as a Breast Imaging Center of Excellence, and has a score above the national average on the Centers for Medicare and Medicaid Services patient recommendation measures, or their equivalents. Fewer than 350 centers met the WCA standards in 2015, resulting in an elite group of centers devoted to women’s breast health.

According to the American Cancer Society, breast cancer is the second most common form of cancer among women. One in eight women will develop breast cancer during her lifetime.

“A multidisciplinary approach is key to assuring the appropriate plan is implemented for each individual patient. We provide our patients with comprehensive, state-of-the-art treatment options and follow-up care that include screening, risk assessment, prevention strategies, diagnosis, treatment, rehabilitation and research, including the latest in clinical trial options.”

“A woman is diagnosed every two minutes, and she needs the knowledge and confidence to select the very best centers that employ advanced technology and clinical practices to give her peace of mind as she embarks on this emotional journey,” said Delia Passi, CEO and founder of the Women’s Choice Award.

The UAB Breast Health Center is part of the UAB Comprehensive Cancer Center, one of the nation’s leading cancer research and treatment centers, and is the only National Cancer Institute-designated comprehensive cancer center located in the six-state area that comprises Alabama, Arkansas, Georgia, Louisiana, Mississippi and South Carolina.

With so many treatment options available, UAB understands the importance of taking a personal, well-rounded approach to each patient’s treatment.

“We know now that breast cancer is not a one-size-fits-all disease,” Krontiras said. “A multidisciplinary approach is key to assuring the appropriate plan is implemented for each individual patient. We provide our patients with comprehensive, state-of-the-art treatment options and follow-up care that include screening, risk assessment, prevention strategies, diagnosis, treatment, rehabilitation and research, including the latest in clinical trial options.”

UAB also has several clinics that match the needs of women, no matter the phase of breast cancer they are battling. Each clinic is staffed by experts in their fields who provide personal care to each and every woman who visits.

“When women choose the UAB Breast Health Center, they can be confident in knowing that our physicians are nationally recognized experts in breast health and employ today’s leading-edge treatments,” said Krontiras.

Marshall Sherfield Fellowships

Marshall Sherfield Fellowships are post-doctoral awards that fund original research for a period of one to two academic years at a British university or research institute. Deadlines for awards are October 7th. Fore more information please visit the Marshall Scholarship website.http://www.marshallscholarship.org/fellowships/applications